This is an application for a competitive renewal of our funding to study the neurobiology of depression. In our first 4.5 years, we have made significant progress on each of our original aims. When we started this research, there was very little support for a role of the nucleus accumbens (NAc) - a brain region implicated in reward and motivation - in depression. Our work has provided clear evidence that activation of the transcription factor CREB (cAMP response element binding protein) within the NAc produces depressive- like signs in rats. The most prominent depressive-like sign is reduced sensitivity to reward (anhedonia), which appears due (at least in part) to CREB-mediated elevations in expression of dynorphin, an endogenous opioid peptide. Our findings provided rationale for studies of drugs that modulate the activity of kappa-receptors, the receptor at which dynorphin acts. We were the first to report that kappa-antagonists produce antidepressant-like effects in rats, and block prodepressant-like effects of kappa-agonists. Collectively, our results suggest that blocking certain consequences of CREB activation (e.g., increased dynophin expresson and subsequent kappa receptor stimulation) in the NAc can relieve key signs of depression, and that kappa-receptor ligands have great utility in the study and treatment of this disorder. The proposed studies will extend these findings, and involve a multidisciplinary blend of genetic mutations, brain microinjections of viral vectors or drugs, and behavioral models of depression. One set of studies is designed to more thoroughly characterize the types of depressive signs that are regulated by CREB in the NAc. For example, it is important to know if elevated CREB function in the NAc alters sensitivity to aversive or anxiety-provoking stimuli. Another set of studies will examine the brain regions in which kappa-agonists and kappa-antagonists produce their mood-relevant effects. Finally, a third set of studies will examine the mechanisms through which kappa-antagonists produce antidepressant-like effects. RELEVANCE: This work should increase our understanding of the brain regions involved in depression, and help to identify the molecular triggers for various depressive behaviors. This knowledge might ultimately contribute to the development of individualized treatments for depression that are safer and more effective because they are tailored to treat the molecular causes of the symptoms directly and selectively.